rs2278741

Variant names:

• chr2-120991491-G-C
• rs2278741
• NM_001374353.1:c.*816G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-120991491-G-C
• chr2-120991491-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):​c.*816G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 152,546 control chromosomes in the GnomAD database, including 29,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29568 hom., cov: 32)
  • Exomes 𝑓: 0.70 (121 hom.)
• Consequence: GLI2 NM_001374353.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.257
• Publications: 13 publications found

Genes affected

GLI2 (HGNC:4318): (GLI family zinc finger 2) This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI2 Gene-Disease associations (from GenCC):

• holoprosencephaly 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-120991491-G-C is Benign according to our data. Variant chr2-120991491-G-C is described in ClinVar as Benign. ClinVar VariationId is 331006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1	c.*816G>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9	c.*816G>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_001374353.1	ENSP00000354586.5

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92169 AN: 151956 Hom.: 29559 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.697 AC: 329 AN: 472 Hom.: 121 Cov.: 0 AF XY: 0.702 AC XY: 205 AN XY: 292

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.701 AC: 300 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.658 AC: 25 AN: 38

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.606 AC: 92185 AN: 152074 Hom.: 29568 Cov.: 32 AF XY: 0.602 AC XY: 44748 AN XY: 74316

African (AFR) AF: 0.397 AC: 16446 AN: 41476

American (AMR) AF: 0.627 AC: 9579 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2455 AN: 5162

South Asian (SAS) AF: 0.510 AC: 2450 AN: 4802

European-Finnish (FIN) AF: 0.661 AC: 6991 AN: 10580

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49653 AN: 67988

Other (OTH) AF: 0.636 AC: 1341 AN: 2110

Alfa AF: 0.551 Hom.: 1731

Bravo AF: 0.592

Asia WGS AF: 0.492 AC: 1709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 9 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.2
DANN	Benign	0.70
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2278741; hg19: chr2-121749067; COSMIC: COSV58040492; COSMIC: COSV58040492;